Benzaldehydes, para-substituted electronic effects

A Hammett plot for para-substituted benzaldehydes showed that electron-rich aldehydes gave higher ees (r = -0.4). As in Shibuya s related results (Section 5.3.3.1 above), this indicates that aldehyde coordination is important in enantiodifferentia-tion, but the lower rvalue (compared to Shibuya s r = -1.30) suggests a weaker electronic influence, probably due to the relative Lewis acidities of A1 and La. For ortho-substituted aldehydes, lower ees were observed, presumably due to steric effects. Although Al-Cl and Al-triflate complexes 29-30a-b did not catalyze the reaction, they... 

The Claisen-Schmidt condensation of 2 -hydroxyacetophenone and different chlorinated benzaldehydes over MgO has been investigated through kinetic and FTIR spectroscopic studies. The results indicate that the position of the chlorine atom on the aromatic ring of the benzaldehyde substantially affects the rate of this reaction. In particular, the rate increases in the following order p-chlorobenzaldehyde < m-chlorobenzaldehyde < o-chlorobenzaldehyde. The difference between the meta and para-substituted benzaldehyde can be attributed to electronic effects due to the difference in the Hammett constants for these two positions. Steric effects were found to be responsible for the higher rate observed with the o-chlorobenzaldehyde. 

Reaction Steps 3a and 3b also can be used to rationalize the observed para-substituent effects presented in Table III the more electron-releasing, para-substituted benzaldehydes retard the rate of oxidative addition (18) for RhCl(PPh3)3. Therefore, p-methyl- and p-methoxybenzaldehyde are expected to be decarbonylated slower than the unsubstituted benzaldehyde, as is observed in Table III. (This argument requires that Reaction 3a be saturated to the right, which is expected, in neat aldehyde solvent with electron-releasing, para-substituted benzaldehydes.) The unexpected slower rate for p-chloro-benzaldehyde could be accounted for ifK for this aldehyde is small and saturation of equilibrium in Equation 3a is not achieved. Note that fcobs is a function of K and k (see Equation 4b) under this condition. It is also possible that the rate-determining step is different for this aldehyde. Present research includes a careful kinetic analysis using several aldehydes so that K and k can be determined independently. 

The effective catalyst 20o ((—)-DFPE) was examined for the ethylation of other aldehydes (Table 3-7). Para-Substituted benzaldehydes, ( )-cinnamaldehyde, 2-furaldehyde, and 2-naphthaldehyde, which possess n electrons adjacent to the carbonyl group, afforded the corresponding secondary alcohols in high enantiomeric purity (entries 1 — 5). In addition, cyclohexanecarboxaldehyde, 2-ethylbutyralde-hyde, and pivalaldehyde, which are branched a. to the carbonyl group, were ethylated in >98% ee (entries 6—11). On the other hand, ethylation of isovaleraldehyde, 3-phenylpropionaldehyde, and n-butyraldehyde, which lack a substituent a to the carbonyl group, proceeded with low selectivity (entries 12 — 14). 

The IL effects can be explained with solvophobic interactions that generate an internal pressure, which promoted the association of the reactants in a solvent cavity during the activation process and showed an acceleration of the multicomponent reactions (MCRs) in comparison to conventional solvents. The reaction proceeded very efficiently with benzaldehyde and electron releasing and electron-withdrawing ortho-, meta-, and para-substituted benzaldehydes. IL was easily separated from the reaction medium by washing with water and distillation of the solvent nnder vacnnm and it can be reused for subsequent reactions and recycled. IL showed no loss of efficiency with regard to reaction time and yield after four successive runs. 

Kinetic and spectroscopic measurements support the hypothesis that the substrate binds directly to the catalytic zinc atom. Dunn and Hutchison (336) have produced evidence using a chromophoric aldehyde as substrate that the carbonyl oxygen of the reaction intermediate is coordinated to zinc. They concluded that zinc acts as a Lewis acid catalyst. Similar conclusions have been reached by McFarland and co-workers from the spectral properties of the enzyme complex with 4- (2 -imidazolyl-azo) benzaldehyde (337), from the observed small electronic substituent effect of para-substituted benzaldehydes (335), and from the absence of a large pH effect in the hydride transfer step (338). Assuming the mechanisms and the subunit structures to be essentially similar in YADH and LADH, a magnetic resonance study of coenzyme and substrate binding to YADH (339) also support the hypothesis of direct binding of substrate to zinc. 

Jacobs et al. (86) have compared the electronic substituent effect on the rate of sodium borohydride reduction vis a vis the LADH-catalyzed reduction (under transient-state kinetic conditions) for a series of para-substituted benzaldehydes. In contrast to the large electronic substituent effect observed in the sodium borohydride reaction (the rate ratio ftp-ci/ p-ocHs is 100), the LADH catalyzed reaction was found to show almost no electronic substituent effect ( p-ci/ p-ocHs —... 

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